That CKD and vascular disease are closely connected has been recognized for several years, although the nature of this connection remains unclear. Among dialysis patients, cardiovascular mortality remains the number one cause of death with rates ranging from 10 to 30 times greater than seen in the general population despite adjustments for other risk factors. In 2003, the American Heart Association released a Scientific Statement outlining the data supporting that CKD patients should be considered in the highest risk group for cardiovascular disease, recognizing the need to treat this patient population aggressively for cardiovascular risk factors. Despite the growing recognition that CKD patients are at greater risk of vascular disease, much remains to be understood as to the mechanisms behind this increased risk. This patient population has a greater prevalence of risk factors for cardiovascular disease, as defined by the Framingham study. However, cross-sectional studies have demonstrated that the Framingham Risk Equation does not adequately predict the magnitude of the increased risk of cardiovascular disease seen in CKD patients. Thus, additional risk factors may be present in CKD patients leading to the increased atherosclerosis beyond those considered most important in the general population. Recent studies suggest that the increased vascular calcification seen in dialysis patients compared with the general population may play a role in the increased risk of cardiovascular events.
Calcification is common in the coronary arteries of dialysis patients, including adolescents and young adults. In patients with known coronary artery disease, those with CKD have been shown to have 2- to 5-fold greater coronary artery calcification, as measured by electron-beam CT scan. Similarly, comparisons of coronary atherosclerotic lesions from age/gender-matched autopsy specimens showed a similar lesion size, but with greater calcification in those patients with end-stage renal disease (ESRD). These data suggest that the atherosclerosis in CKD patients may progress at a similar rate as normal patients, but with greater calcification. Increased calcification is also seen in the peripheral vasculature of CKD patients. Several studies of ESRD patients have indicated an increased stiffness in the larger arteries resulting in increases in pulse wave velocities and pulse pressures as well as mortality. Pulse wave velocities and pulse pressures have also been demonstrated to be proportional to the magnitude of calcification as detected by ultrasound. Histological studies have demonstrated an increased intimal thickness, intimal calcification, and medial calcification in the renal arteries of dialysis patients compared with age-matched autopsy specimens. Other studies have demonstrated a similar increase in the calcification of the iliac and radial arteries of dialysis patients.
Previous data from our laboratory, comparing the degree of coronary artery calcification in patients with varying plasma creatinine levels, also support these findings. Plasma creatinine levels are commonly used to assess the renal function of a patient with higher values indicating decreased function. We grouped the patients by plasma creatinine quintiles and compared the mean coronary calcium scores obtained using a Philips Mx-8000 16 detector CT scanner (FIG. 1). Our hypothesis was that CKD patients will have increased levels of proteins with osteogenic potential, such as the BMP family, in their plasma leading to an increase in the vascular calcification seen in this patient population. These data support our hypothesis by demonstrating that patients with decreased kidney function have elevated levels of coronary artery calcification. Taken together these data demonstrate that CKD patients have greater vascular calcification, and that this increase in vascular calcification may play an important role in the increased risk of CKD patients for coronary artery disease (CAD).
Diagnostic and therapeutic radiological procedures require the use of iodinated contrast media. These procedures include diagnostic catheterizations to determine the presence of vascular disease and percutaneous coronary interventions (PCI, commonly referred to as balloon angioplasty) for the treatment of CAD. A minor and temporary decrease in glomerular filtration rate, an indication of impaired renal function, is common in patients undergoing radiological procedures using iodinated contrast media. In a small percentage of the general population a more severe impairment of renal function occurs that is referred to as contrast-induced nephropathy (CIN, also known as radiocontrast nephropathy or contrast associated nephropathy). CIN is defined as an increase in absolute serum creatinine >0.05 mg/dL or in relative creatinine of >25%, and occurs in ˜1.2 to 1.6% of the general population. While overall CIN rates are low, the occurrence of CIN is extremely high in certain high risk patients, including CKD patients, making it the leading cause of morbidity and mortality in this patient group following PCI. The incidence of CIN in patients with impaired renal function prior to PCI has been reported to be as high as 55%. Furthermore, several studies have demonstrated that the risk of CIN increases with an increase in serum creatinine, an indicator of CKD. Those patients that develop CIN exhibit an increase in morbidity and in both in-hospital and long-term mortality. To date no clearly effective method to prevent CIN has been found, making early identification of high risk patients coupled with careful management of the extent of their exposure to contrast media the best method to prevent CIN. The ability to identify those CKD patients with an increased risk of CAD through the measurement of BMP-4 serum levels will allow the physician to more accurately differentiate those CKD patients that require aggressive CAD treatments such as PCI from those who might forego exposure to contrast media due to a diminished risk of CAD. Currently no such clinical test exists.
Over the past ten years, it has become clear that vascular calcification occurs through a cell-mediated active process. First, the deletion of certain genes (e.g. matrix gla protein and osteoprotegrin) has been shown to increase vascular calcification in animals. Histological analysis has demonstrated the presence of several osteogenic proteins in regions of arterial calcification. This led to the hypothesis that cells in the vessel wall dedifferentiate into an osteoblast-like state, and that vascular calcification occurs through a mechanism similar to that of normal bone production. VSMCs have been shown to undergo dedifferentiation to an osteoblast-like state in vitro, and calcifying vascular cells have been isolated from primary VSMC cultures. Others have suggested that pericytes migrate from the adventia to the media and intima and differentiate into an osteoblast-like state. Finally, circulating mesenchymal stem cells may also accumulate at sites of vascular injury and differentiate into an osteoblast-like cell. Despite this debate, it is clear that cells within the calcified regions of the vasculature express proteins that are not normally found in VSMCs or fibroblasts and are associated with osteogenesis. One mechanism proposed for the induction of these proteins is the up-regulation of the bone morphogenic proteins (BMPs) at the site of vascular calcification.